In-silico studies and Biological activity of potential BACE-1 Inhibitors

2020 ◽  
Vol 23 ◽  
Author(s):  
Richa Arya ◽  
Sarvesh Paliwal ◽  
S.P Gupta ◽  
Swapnil Sharma ◽  
Kirtika Madan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Biological Activity ◽  
In Silico ◽  
Neuronal Damage ◽  
Pharmacophore Model ◽  
Vitro Assay ◽  
App Processing ◽  
In Silico Studies ◽  
Bace 1

Background: Alzheimer’s disease is neurological condition causing cognitive inability and dementia. The pathological lesions and neuronal damage in brain is caused by self-aggregated fragments of mutated Amyloidal precursor protein (APP). Objective: : The controlled APP processing by inhibition of secretase is the strategy to reduce Aβ load to treat Alzheimer’s disease. Method: A QSAR study was performed on 55 Pyrrolidine based ligands as BACE-1 inhibitors with activity magnitude of greater than 4.of compounds. Results: In an advent to design new BACE-1 inhibitors, the pharmacophore model with correlation (r = 0.90) and root mean square deviation (RMSD) of 0.87 was developed and validated. Further, the hits retrieved by in-silico approach were evaluated by docking interactions. Conclusion: Two structurally diverse compounds exhibited Asp32 and Thr232 binding with the BACE-1 receptor. The aryl substituted carbamate compound exhibited highest fit value and docking score. The biological activity evaluation by in-vitro assay was found to be >0.1µM.

Pharmacophore Modeling and Docking Studies to Investigate Potential Leads for the Development of β -Secretase APP Cleavage Enzyme-1 (BACE-1) Inhibitors

2019 ◽  
Vol 16 (7) ◽  
pp. 775-784
Author(s):  
Richa Arya ◽  
Satya Prakash Gupta ◽  
Sarvesh Paliwal ◽  
Swapnil Sharma ◽  
Kirtika Madan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Medical Condition ◽  
Pharmacophore Model ◽  
Pharmacophore Modeling ◽  
Docking Studies ◽  
Pyridine Derivative ◽  
Cleavage Enzyme ◽  
Bace 1

Background: Alzheimer’s disease is a medical condition with detrimental brain health. It is majorly diagnosed in aging individuals plaque in β) characterized by accumulated Amyloidal beta (A 1 BACE) 1 secretase APP cleavage enzyme βneurological areas. The ) is the target of choice that can be exploited to find drugs against Alzheimer’s disease. Methods: A series of BACE-1 inhibitors with reported binding constant were considered for the development of a feature based pharmacophore model. Results: The good correlation coefficient (r=0.91) and RMSD of 0.93 was observed with 30 compounds in training set. The model was validated internally (r2test=0.76) as well as externally by Fischer validation. The pharmacophore based virtual screening retrieved compounds that were docked and biologically evaluated. Conclusion: The three structurally diverse molecules were tested by in-vitro method. The pyridine derivative with highest fit value (6.9) exhibited IC50 value of 2.70 µM and thus was found to be the most promising lead molecule as BACE-1 inhibitor.

In silico screening of pyridoxine carbamates for Anti-Alzheimer’s activities

2020 ◽  
Vol 20 ◽  
Author(s):  
Dnyaneshwar Baswar ◽  
Abha Sharma ◽  
Awanish Mishra
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
In Silico ◽  
Neurodegenerative Disorder ◽  
Biological Activities ◽  
Cholinergic Neurons ◽  
In Silico Screening ◽  
In Silico Studies ◽  
Bbb Permeability ◽  
Ld50 Value

Background: Alzheimer’s disease (AD), an irreversible complex neurodegenerative disorder, is most common type of dementia, with progressive loss of cholinergic neurons. Based on the multi- factorial etiology of Alzheimer’s disease, novel ligands strategy appears as up-coming approach for the development of newer molecules against AD. This study is envisaged to investigate anti-Alzheimer’s potential of 10 synthesized compounds. The screening of compounds (1-10) was carried out using in silico techniques. Methods: For in silico screening of physicochemical properties of compounds molinspiration property engine v.2018.03, Swiss ADME online web-server and pkCSM ADME were used. For pharmacodynamic prediction PASS software while toxicity profile of compounds were analyzed through ProTox-II online software. Simultaneously, molecular docking analysis was performed on mouse AChE enzyme (PDB ID:2JGE, obtained from RSCB PDB) using Auto Dock Tools 1.5.6. Results: Based on in silico studies, compound 9 and 10 have been found to have better drug likeness, LD50 value, and better anti-Alzheimer’s, nootropic activities. However, these compounds had poor blood brain barrier (BBB) permeability. Compound 4 and 9 were predicted with better docking score for AChE enzyme. Conclusion: The outcome of in silico studies have suggested, out of various substitutions at different positions of pyridoxine-carbamate, compound 9 have shown promising drug likeness, with better safety and efficacy profile for anti-Alzheimer’s activity. However, BBB permeability appears as one the major limitation of all these compounds. Further studies are required to confirm its biological activities.

scholarly journals Functionalized aromatic esters of the Amaryllidaceae alkaloid haemanthamine and their in vitro and in silico biological activity connected to Alzheimer’s disease

2020 ◽  
Vol 100 ◽  
pp. 103928
Author(s):  
Rozálie Peřinová ◽  
Negar Maafi ◽  
Jan Korábečný ◽  
Eliška Kohelová ◽  
Angela De Simone ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Biological Activity ◽  
In Silico ◽  
Aromatic Esters

scholarly journals β-Carotene: A Natural Compound Improves Cognitive Impairment and Oxidative Stress in a Mouse Model of Streptozotocin-Induced Alzheimer’s Disease

Biomolecules ◽  
2019 ◽  
Vol 9 (9) ◽  
pp. 441 ◽  
Author(s):  
Sundas Hira ◽  
Uzma Saleem ◽  
Fareeha Anwar ◽  
Muhammad Farhan Sohail ◽  
Zohaib Raza ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
In Silico ◽  
Control Group ◽  
Enhancement Effect ◽  
Amyloid Β Protein ◽  
Group I ◽  
In Silico Studies ◽  
Β Carotene

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by a cascade of changes in cognitive, behavioral, and social activities. Several areas of the brain are involved in the regulation of memory. Of most importance are the amygdala and hippocampus. Antioxidant therapy is used for the palliative treatment of different degenerative diseases like diabetes, cirrhosis, and Parkinson’s, etc. The objective of this study was to assess the effectiveness of exogenous antioxidants, in particular, β carotene (1.02 and 2.05 mg/kg) against intracerebroventricular injected streptozotocin-induced memory impairment in mice. Streptozotocin (3 mg/kg, i.c.v) was administered in two separate doses (on 1st and 3rd days of treatment) for neurodegeneration. Fifty Albino mice (male) were selected in the protocol, and they were classified into five groups (Group I—control, Group II—disease, Group III—standard, Group IV–V—β-carotene-treated) to investigate the cognitive enhancement effect of selected antioxidants. The cognitive performance was observed following the elevated plus-maze, passive avoidance, and open field paradigms. Acetylcholine esterase, β-amyloid protein, and biochemical markers of oxidative stress such as glutathione peroxidase, superoxide dismutase, and catalase were analyzed in brain homogenates. In silico activity against acetylcholinesterase (AChE) was determined by the molecular modeling of β-carotene. β-carotene at a dose of 2.05 mg/kg was found to attenuate the deleterious effects of streptozotocin-induced behavioral and biochemical impairments, including the inhibition of acetylcholinesterase activity. The in silico studies confirmed the binding capacity of β-carotene with the acetylcholinesterase enzyme. The administration of β-carotene attenuated streptozotocin-induced cognitive deficit via its anti-oxidative effects, inhibition of acetylcholinesterase, and the reduction of amyloid β-protein fragments. These results suggest that β-carotene could be useful for the treatment of neurodegenerative diseases such as Alzheimer’s disease.

In-silico study of some natural plant phyto-compounds for the identification of novel potent cholinesterase inhibitors against Alzheimer's Disease

2021 ◽  
Vol 12 (3) ◽  
pp. 243-250
Author(s):  
Dhiraj Kumar ◽  
Sanjana Bhagat
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Binding Affinity ◽  
In Silico ◽  
Docking Study ◽  
Inhibitory Effect ◽  
Ache Inhibitor ◽  
Strong Binding ◽  
In Silico Studies ◽  
Autodock 4.0

The main aim of this study is to identify inhibitory binding potent of the available commercially alkaloids, against the crystal structure of acetylcholinesterase (AChE) protein by in silico studies. The inhibitory data of the compounds should be compared with the internal ligand as well as standard AChE inhibitor Aricept (which is used for the treatment of all stages of Alzheimer’s disease). AutoDock 4.0 is used for the docking study, conformational orientation site analysis, and, with the help of docking, we have calculated parameters like binding energy and inhibition constant. Docking's study showed that Glabridin, Isorosmanol, Quercetin, Honokiol, Eckol, Sargaquinoic acid, and Ginsedosides revealed strong binding affinity with the enzyme. Moreover, The ADMET profiling and physicochemical properties of the selected compounds are evaluated using the Molinspiration and Data warrior software. By showing a strong binding affinity value, positive bioactivity score, and good pharmacokinetic properties, the top compound was determined. After evaluation with all parameters, the compound Glabridin and Ginsedosides show the most potent inhibitory effect towards the acetylcholinesterase, so this compound could be used as a novel is required to treat Alzheimer's disease.

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